The transdermal route of administration of therapeutically active drugs has been used by investigators to deliver the drugs into the systemic circulation of mammals, including humans. However, despite the development of various means for the transdermal delivery of drugs, the skin of humans and other animals provides an excellent barrier to the penetration of chemical substances that are exogenously applied. The outermost layer of skin, the stratum corneum, offers maximum resistance to penetration, while the lower skin layers are relatively more permeable. For the proper treatment of skin disorders and diseases, it is important that the pharmacologically active agent penetrate the stratum corneum and be made available at appropriate concentrations at the site of action, which can be the stratum corneum, the viable epidermis, the epidermis-dermis junction, the dermis per se, or all of the aforementioned layers of the skin, depending upon the type of skin disorder or skin disease condition.
Various dermal effective pharmacological agents are known which can provide beneficial effects when applied topically to the skin to treat surface or subsurface diseases or for creating skin conditions which protect the skin from external factors. Other pharmacological agents are also known which can provide beneficial effects when absorbed into the systemic circulation. Thus, it is possible to have a systemic effect through topical application of a composition. The topical delivery of systemically effective pharmacological agents can be of significant value in cases where drugs produce gastric problems, are not well absorbed when given orally, or are rapidly metabolized in the liver, e.g. the "first pass" effect. In such cases, the use of topical delivery can give a systemic response at lower dosage than required orally. Topical delivery also avoids the disadvantages present in the intravenous route of administration, which might otherwise be required in order to achieve effective blood levels at reasonable dosage amounts. In addition, dermatological agents can be made more beneficial by enhancing their penetration through the protective layer of the skin in accordance with the present invention.
In certain dermatological conditions or pathologies, such as ichthyosis, callus, or plaque psoriasis, the stratum corneum is thicker and therefore can provide a significantly greater barrier to penetration of a drug, thus reducing its efficacy. Moreover, recent studies have shown that with increasing age, a person's skin becomes more resistant to penetration by water soluble drugs. In a few disease conditions, for example, psoriasis, the stratum corneum is not intact and hence is more permeable than that of normal skin. As the disease or condition improves, there is restructuring of the barrier, and resistance to the permeation of the therapeutically active agent will increase.
The use of penetration or permeation enhancers has been found to be critical to achieve a consistent supply of a therapeutically active ingredient at the site of action during the treatment of skin diseases. For example, as described in U.S. Pat. No. 5,326,566, a composition of such systemically effective pharmacological agents in combination with dibutyl adipate, or a mixture of dibutyl adipate and isopropyl myristate, can greatly enhance the rate of penetration of agents through the skin and can increase the amount absorbed into the systemic circulation. Although a variety of permeation enhancing agents have been used for enhancing the absorption of therapeutic agents into and through the skin, serious problems can arise when permeation enhancers are incompatible with a given drug over a long time period, thereby resulting in drug instability and degradation when the enhancers and the drug are co-formulated into a pharmaceutically acceptable composition for use in warm-blooded mammals, including humans. As a consequence, the practitioner in the art is hampered by an inability to employ certain permeation enhancers for increasing the skin permeation of a drug, if the permeation enhancer and the drug cannot be mixed and stored together without the drug becoming unstable over time and degrading to produce unwanted and potentially harmful byproducts. In addition to the formation of such drug breakdown products, there is also a risk of administering these breakdown products into the circulation of a warm-blooded mammal, including human patients, along with the active drug. Thus, if a drug has demonstrated efficacy in treating a particular affliction of the skin and related tissues, but has a low rate of skin permeation and is unstable for long-term formulation with and storage in permeation enhancing compositions, the utility of such drugs for medical and clinical development and for personal use is greatly diminished, if not abolished. Accordingly, in view of the foregoing, and because, upon storage, the permeation enhancer degrades the drug in question, or vice versa, one skilled in the art would be led away from using the permeation enhancer with particular drugs with particular permeation enhancers, and vice versa.
Moreover, in certain instances, the permeation enhancer may be incompatible with a drug and/or the composition containing the drug over a long time period, thereby resulting in instability of the permeation enhancer and its degradation when the permeation enhancer and the drug are co-formulated into a pharmaceutically acceptable composition for use in warmblooded mammals, including humans. As a consequence, one skilled in the art is hampered by an inability to employ certain permeation enhancers for increasing skin permeation of a drug, if the permeation enhancer and the drug cannot be mixed and stored together in a pharmaceutically acceptable composition without the permeation enhancer becoming unstable over time and degrading to produce unwanted and potentially harmful products.
Accordingly, the present invention allows drugs having a generally low rate of skin permeation to be used with a permeation enhancer to significantly improve the rate of skin penetration of the drug after topical application by providing separate formulations of the drug, in an appropriate pharmacological vehicle, and of the permeation enhancer, preferably in an appropriate pharmacological vehicle, wherein the drug and the permeation enhancer are combined and mixed at the site of application on the skin only at or shortly before the time of topical application on the skin.
The present invention also provides a solution to the instability problem encountered when a drug having a low rate of skin permeation is used with a permeation enhancer which does not have long-term stability in the composition containing the drug. The invention allows a drug having a low rate of skin permeation to be used with a permeation enhancer having instability with the drug and/or a composition containing the drug to improve significantly the rate of skin permeation of the drug after topical application on the skin by providing three separate formulations: one of drug, another of permeation enhancer, and yet another of a vehicle. The drug, permeation enhancer, and vehicle formulations are combined and mixed at the site of application only at or shortly before the time of application on the skin.
In certain instances a drug having a low rate of skin permeation and a permeation enhancer may be compatible with each other, but one or both may not have long-term stability in the vehicle for the drug. In such instances, the use of the present invention will significantly improve the skin permeation of the drug after its topical application by providing two separate formulations: one formulation containing the drug plus the permeation enhancer and the second containing vehicle. The formulation containing the drug and permeation enhancer and the formulation containing the vehicle is combined and mixed at the site of application only at or shortly before the time of application on the skin.
Thus, as a result of the present invention, the rate of skin penetration of a drug in the active composition is greatly enhanced over the penetration rate of the drug in the absence of enhancer. In addition, the present invention provides a solution to the aforementioned problems in the art by allowing those skilled in the art to utilize a permeation enhancer with a drug, regardless of a low penetration rate of the drug, or the incompatibility of the drug with particular permeation enhancers, or vice versa, after being combined therewith.
Grollier et al., U.S. Pat. No. 4,823,985, teaches the use of a dispensing assembly for at least two constituents used in hair coloration and having specified viscosities to enable the common dispensing of the constituents and the production of a composition on a site of application. Grollier et al. describe the preparation of cosmetic products for hair care and, unlike the present invention, are not concerned with the permeation-enhanced, transdermal delivery of a drug having a low permeation rate and an incompatibility with a permeation enhancing agent with which it is combined.
Petersen et al., U.S. Pat. No. 5,156,846, discloses a percutaneous drug delivery system and method which requires pretreating the skin with a skin permeation enhancer, which is an enzyme preparation, and occluding the area of the skin to which the skin permeation enhancing enzyme preparation is applied, removing the skin occlusion means, and applying a drug after rinsing the area. It is disclosed that the skin can again be occluded following application of the drug on the enzyme-pretreated site.
Y. Chang, U.S. Pat. No. 4,956,171, teaches a transdermal drug delivery system having a dual permeation enhancer in which the specific permeation enhancers are sucrose cocoate and methyl laurate. These two enhancers are required for use due to their ability to synergize for penetration enhancement. Unlike the present invention, the disclosure does not relate to a drug and/or permeation enhancer that are unstable during long-term storage with certain permeation enhancers and/or drugs, respectively, which may induce degradation of the drug and/or permeation enhancer, but which can also increase the permeation of the drug when the drug and enhancer are mixed on the skin at the point of use.
German Patent Application No. DE4435805-A1 discloses formation of an enzyme cream at the site of application from an enzyme containing anhydrous ointment base and an aqueous tenside containing oily emulsion (or a mixture of emulsifiers) which are packaged separately. The cream is disclosed to provide enzyme stability and maximum activity at the application site. This patent application deals with an incompatibility between an enzyme and an emulsion vehicle, with the purpose being to maintain enzyme activity at the site of application. This application does not involve or suggest a method and means to increase and enhance the permeation level of a drug which, in the absence of permeation enhancer, has a low level of skin permeation, but which is unstable in the presence of permeation enhancer.
Klein et al., U.S. Pat. No. 4,497,794, discloses a method and composition for the topical treatment of acne, which require the use of the drugs benzoyl peroxide and erythromycin, or derivatives thereof. The patent is not concerned with permeation enhancers and discloses that the two required drug components may be applied to the skin as a mixture or separately applied to the skin; however, unlike the present invention, peroxide, particularly benzoyl peroxide, synergizes with erythromycin. The patentees disclose that erythromycin and benzoyl peroxide, though chemically incompatible, were rendered stable by adding the surfactant, dioctyl sodium sulfosuccinate, to the disclosed benzoyl peroxide/erythromycin gel composition. By contrast, the present invention requires no additives to stabilize the permeation enhancer composition.
Campbell et al., U.S. Pat. No. 4,379,454, discloses a means for delivering to a defined area of skin a co-administered and controlled dosage of a drug and a percutaneous absorption enhancer, with particular regard to a dosage form and method for co-administering estradiol and ethanol percutaneously to treat conditions associated with natural estradiol deficiency.
WO 92/09266, Beecham Group, discloses a two-phase composition for topical drug application in which there are two liquid phases having different lipophilicities. Drug is dissolved in one of the phases such that a supersaturated state with respect to drug must result after mixing the liquid phases.
WO 92/17183, Glaxo, Inc., discloses a sequential dosing medicament and method therefor for topical treatment of fungal infections. The medicament comprises a first composition having an antifungal agent and an anti-inflammatory agent, and a second composition having only an antifungal agent as the active ingredient.
Accordingly, the present invention provides the transdermal delivery of a variety of types of drugs, which otherwise have low permeation rates and are generally incompatible with skin permeation enhancers during long-term combination, at therapeutically effective and significantly increased skin penetration rates, when used and applied as described herein. The present invention further provides the co-delivery and combining of drug having a low rate of skin permeation and a permeation enhancer which is unstable when mixed with the drug (or with vehicle for the drug) over a long period of time. In contrast to the art, the drug and permeation enhancer components of the invention are not permitted to interact prior to use, as a result of their physical separation in a suitable delivery device after preparation and during storage, before being topically applied and mixed on the skin at the site of application. Conveniently, the level or extent of penetration of the drug into the skin is advantageously and highly increased at the time of or shortly before use by mixing or blending the drug and permeation enhancer compositions directly on the skin to produce the desired active composition on the site of application by the user or applier.